Macroautophagy in Major Histocompatibility Complex (MHC) class I-restricted Antigen Presentation

Abstract

Autophagy is a physiological, conserved catabolic process by which cytoplasmic material is delivered for degradation into lysosomes. Autophagy plays a role in several cellular processes and in various aspects of immunity but its role in trafficking pathways and major histocompatibility complex (MHC) class I presentation has only been poorly described. Here, we show that molecular machinery of autophagy regulates MHC class I surface levels and intracellular antigen presentation in vitro and in vivo. Briefly, it has been found that MHC class I molecules are stabilized on the cell surface of murine antigen presenting cells deficient for core components of autophagy, such as ATG5 or ATG7. This stabilization seems to result from defective internalization of MHC class I molecules dependent on adaptor protein kinase 1 (AAK1), a member of clathrin-dependent endocytosis machinery. Indeed, AAK1 interacts with the cytosolic form of LC3 (Microtubule-associated protein 1A/1B-light chain 3), a pivotal molecule of autophagy, and it is recruited to the MHC class I internalization machinery upon LC3 lipidation. Therefore, when autophagy and specifically, LC3 lipidation is blocked, MHC class I molecules get stabilized on the surface of dendritic cells resulting in a more efficient stimulation of CD8+ T cell responses in vitro and in vivo. Importantly, the absence of autophagy-dependent internalization during viral infections, such as influenza virus and lymphocytic choriomeningitis virus, leads to enhance virus-specific CD8+T cell responses in vivo and a better immune control of influenza infection. Additionally, preliminary studies using B cells infected by Epstein Barr virus and deficient for the transporter-associated with antigen presentation (TAP), a key protein in the MHC class I presentation pathway, suggest a contribution of autophagy in the regulation of intracellular MHC class I antigen presentation. Indeed, preliminary data show that autophagy might contribute to deliver antigens as well as to supply MHC class I molecules to an endosomal compartment for an alternative MHC class I antigen processing and presentation as a consequence of the impairment of classical MHC class I antigen processing. These findings clearly show that the autophagy machinery orchestrates T cell immunity by regulating MHC class I surface expression levels and it can also help to improve adaptive immune response against viral pathogens by circumventing viral immune escape mechanisms.